Uroporphyria produced in mice by iron and 5-aminolaevulinic acid does not occur in Cyp1a2(-/-) null mutant mice.
In the present study we have investigated the putative requirement for the cytochrome P-450 isoform CYP1A2 in murine uroporphyria, by comparing Cyp1a2(-/-) knockout mice with Cyp1a2(+/+) wild-type mice. Uroporphyria was produced by injecting animals with iron-dextran and giving the porphyrin precursor 5-aminolaevulinic acid in the drinking water. Some animals also received 3-methylcholanthrene (MC) to induce hepatic CYP1A2. In both protocols, uroporphyria was elicited by these treatments in the Cyp1a2(+/+) wild-type mice, but not in the null mutant mice. Uroporphyrinogen oxidation activity in hepatic microsomes from untreated Cyp1a2(+/+) mice was 2.5-fold higher than in Cyp1a2(-/-) mice. Treatment with MC increased hepatic CYP1A1 in both mouse lines and hepatic CYP1A2 only in the Cyp1a2(+/+) line, as determined by Western immunoblotting. MC increased hepatic ethoxy- and methoxy-resorufin O-dealkylase activities in both mouse lines, but increased uroporphyrinogen oxidation activity in the Cyp1a2(+/+) wild-type mice only. These results indicate the absolute requirement for hepatic CYP1A2 in causing experimental uroporphyria under the conditions used.
Sinclair
P R
PR
VA Medical Center, White River Junction, VT 05009, USA.
Gorman
N
N
Dalton
T
T
Walton
H S
HS
Bement
W J
WJ
Sinclair
J F
JF
Smith
A G
AG
Nebert
D W
DW
D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011164:Porphyrias / Q000139:chemically induced*; D014577:Uroporphyrinogens / Q000378:metabolism; D014578:Uroporphyrins / Q000652:urine*
D014577:Uroporphyrinogens; D014578:Uroporphyrins; D008748:Methylcholanthrene; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2